High-risk Papillary Thyroid Carcinoma Research Articles

Correlation between Contrast-enhanced Ultrasound and Risk of Tumor Recurrence in Papillary Thyroid Carcinoma

Objective To explore the association between contrast-enhanced ultrasound and risk of tumor recurrence in papillary thyroid carcinoma(PTC). Methods A total of 287 PTCs in 287 patients who underwent surgery,conventional ultrasound,and contrast-enhanced ultrasound(CEUS)were enrolled in this study.According to 2015 American Thyroid Association(ATA)Modified Initial Risk Stratification System,the patients were categorized into three groups:low risk,intermediate risk,and high risk.The CEUS patterns of PTCs were compared between different risk stratifications. Results Hypo-enhancement was presented in 57.6% of ATA low-risk PTCs,iso-enhancement in 62.3% of ATA intermediate-risk PTCs,and hyper-enhancement in 48.2% of ATA high-risk PTCs(P<0.0001).The risk stratifications and enhanced intensity in PTC showcased a positive correlation(Spearman's rho of 0.442,P<0.0001)and a linear trend(χ 2 value of 55.921,P<0.0001).Higher enhancement intensity corresponded to higher risk stratification.Ordinal logistic regression analysis indicated that PTCs with hyper-enhancement and iso-enhancement presented higher risks than those with hypo-enhancement after age and gender were adjusted,and theOR values were 17.5(8.4-36.2)and 3.4(2.0-5.8),respectively. Conclusions CEUS patterns correlate intimately with the recurrence risk in PTC.Hyper-enhancement PTCs tend to present high risks,while hypo-enhancement PTCs tend to present low risks of recurrence.

Indications and outcomes of superselective neck dissection: A review and analysis of the literature.

Superselective neck dissection, defined as dissection of two or less contiguous neck levels, has recently been introduced to reduce surgical morbidity of neck dissection while maintaining favorable oncologic outcomes. The purpose of this review is to report the results of superselective neck dissection when applied to specific settings: the management of regional disease after chemoradiation, head and neck squamous cell carcinoma with clinical N0 necks, and high risk papillary thyroid carcinoma.

Predictors of recurrence after total thyroidectomy plus neck dissection and radioactive iodine ablation for high-risk papillary thyroid carcinoma.

American Thyroid Association (ATA) proposed management guidelines for differentiated thyroid cancer, including a three-tiered risk stratification system for structural recurrence. This study aimed to compare the various 2015 ATA criteria for the strength of association with the recurrence of high-risk papillary thyroid carcinoma (PTC). This study included 545 consecutive patients who underwent total thyroidectomy plus neck dissection and radioactive iodine ablation (RAI) for previously untreated high-risk PTC. The association of recurrence-free survival (RFS) with clinicopathological factors was evaluated by univariate and multivariate Cox proportional hazard regression analyses. During a follow-up median period of 89 months, 90 (16.5%) patients had any-site recurrence. Of the high-risk factors, high stimulated thyroglobulin (sTg) level and >3-cm sized lymph nodes (LNs) were significantly associated with recurrence (all P < .005). Sex, tumor size, lymphovascular invasion, multifocality, number of positive LNs, extranodal extension, T and N classifications, and overall tumor-node-metastasis stage were also significantly associated with recurrence (all P < .05). In multivariate analyses, high sTg level [adjusted hazard ratio (HR) = 7.18] and N1b (adjusted HR = 3.27) were independent factors predictive of recurrence (all P ≤ .001). Postoperative high serum sTg level might be the most important predictor of PTC recurrence after total thyroidectomy plus neck dissection and RAI.

Coexistence of BRAFV600E mutation and EGFR overexpression is highly associated with adverse clinicopathological features of papillary thyroid carcinoma

Papillary thyroid carcinoma (PTC) generally has a good prognosis, but in a subset of patients it progresses to aggressive forms. Analysis of molecular alterations in relation to clinical phenotype may help in risk stratification of patients by predicting tumor aggressiveness. We analyzed the expression profiles of epidermal growth factor receptor (EGFR) using immunohistochemistry and the presence of BRAF(V600E) mutation by mutant allele-specific PCR in PTC tissue samples (n=92) in relation to clinicopathological parameters. BRAFV600E was detected in 46.7% of patients and correlated with the presence of lymph node metastasis (LNM, p=0.035) and extrathyroid invasion (EI, p&lt;0.0001). EGFR overexpression was detected in 52.2% of the patients and also correlated with LNM (p&lt;0.0001) and EI (p=0.027). Among patients with a single alteration, the presence of BRAFV600E impacted EI, while EGFR overexpression alone had a greater impact on LNM. The strongest association with adverse features was found in PTC patients with coexisting BRAFV600E and EGFR overexpression (28.3%), among whom LNM and EI were evident in 73% and 69%, respectively (p&lt;0.0001, for both). Thus, the coexistence of BRAFV600E mutation and EGFR overexpression identifies high-risk PTC patients, who should be considered for combined molecular therapy offering a better long-term therapeutic outcome.

Papillary thyroid carcinoma is a risk factor for severe osteoporosis.

Thyroid-stimulating hormone (TSH)-suppressive therapy is recommended after surgical treatment in high-risk papillary thyroid carcinoma (PTC) patients. TSH-suppressive therapy is a known risk factor for osteoporosis and fractures. However, whether patients with PTC themselves are at a higher risk of osteoporosis than healthy individuals remains unclear. This study aimed to clarify whether PTC is a risk factor for osteoporosis. Serum and urinary biochemical parameters, bone mineral density (BMD), and presence of vertebral fractures (VFs) and non-VFs were evaluated in 35 PTC patients and 35 age- and sex-matched healthy individuals. We compared the parameters between PTC and control subjects and performed multiple logistic regression analyses after adjustments for variables. Patients with PTC had higher body mass index (BMI) and hemoglobin (Hb)A1c, as well as lower eGFR and intact PTH than controls (p < 0.05, each). There were no significant differences in the prevalence of osteoporosis and VFs and non-VFs between patients with PTC and controls. However, the prevalence of severe osteoporosis diagnosed according to WHO criteria was significantly higher in PTC subjects (34.3%) than in controls (11.4%, p < 0.05). Multivariate logistic regression analyses adjusted for age, BMI, eGFR and HbA1c identified PTC as being associated with the presence of severe osteoporosis (odds ratio, 4.20; 95% confidence interval, 1.05-16.8; p < 0.05). We identified PTC as a risk factor for severe osteoporosis, independent of BMI, renal function and glucose profile.

The prognostic value of the lymphocyte-to-monocyte ratio for high-risk papillary thyroid carcinoma.

Background and AimsThe prognosis of papillary thyroid carcinoma (PTC) is highly variable, even for high-risk cases. The predictive and prognostic role of the lymphocyte-to-monocyte ratio (LMR) has been reported in other cancers. The aim of our present study was to explore the value of LMR prognostic prediction in high-risk PTC patients.Patients and MethodsTwo hundred and twenty-four PTC high-risk cases at West China Hospital were randomized into a training set (112 cases) and testing set (112 cases), while 48 cases in Shang Jin Nan Fu Hospital were included as the external validation set.ResultsA lower preoperative LMR correlated with larger tumor size, advanced N and M stages, and an increased number of multiple PTC cases in the training, testing, and validation sets (all P<0.05 in the three sets). Patients with a high LMR exhibited significantly improved overall and PTC-free survival compared with those of patients with a low LMR in the training, testing, validation, and combined sets (all P<0.05 in the individual and combined sets). Moreover, multivariate analyses identified the LMR as an independent prognostic factor for overall and PTC-free survival. The nomograms for predicting the 5-year mortality and PTC recurrence were developed based on the risk factors in the training set and validated in the independent testing and validation sets.ConclusionThe preoperative LMR was identified as an independent prognostic factor that could be incorporated into the two nomograms with other risk factors to predict overall survival and PTC-free survival for individual patients.

Impact of delayed radioiodine therapy in intermediate-/high-risk papillary thyroid carcinoma.

It remains unclear whether the time interval between total thyroidectomy and radioactive iodine therapy (RAIT) affects clinical outcomes in papillary thyroid carcinoma (PTC). Therefore, we evaluated the impact of timing of the first post-thyroidectomy RAIT in intermediate-to-high-risk PTC. This retrospective propensity score-matched cohort study included 720 PTC patients who received RAIT for <90 or 90-180days (early and delayed groups, n=360 each) after thyroidectomy. Responses to therapy, disease-free survival (DFS) and overall survival (OS) were compared between the two groups. After matching, the baseline characteristics of the 360 patients in each group were similarly adjusted. Within the first 2years after initial therapy, the number of patients classified into excellent, indeterminate, biochemical incomplete and structural incomplete response categories were 221 (61%), 74 (21%), 39 (11%) and 26 (7%) in the early group, and 204 (57%), 73 (20%), 59 (16%) and 24 (7%) in the delayed group, respectively. There was no significant difference in response to therapy between the two groups (P=0.183). During the median follow-up of 8.6years, there was no significant difference in DFS (P=0.060) and OS (P=0.400) curves between the two groups. Delayed RAIT was not significantly associated with worse DFS (HR=1.3, 95% CI 0.9-1.8, P=0.061) or OS (HR=1.5, 95% CI 0.6-3.4, P=0.388). Delaying the first RAIT until 180days after total thyroidectomy had no impact on restaging, recurrence and mortality in intermediate-to-high-risk PTC.

Genistein inhibits human papillary thyroid cancer cell detachment, invasion and metastasis.

Papillary thyroid carcinoma (PTC) is the most commonly diagnosed endocrine cancer, and those with BRAFV600E mutation have high recurrence rate and less favorable clinical behavior. Genistein having anti-carcinoma effects in various types of carcinomas as an estrogen analog, but the mechanism of Genistein in the progression of PTC remains unknown. Genistein significantly inhibits the proliferation and the invasion (P < 0.01), and the apoptosis (P < 0.001) of all tumor cell lines, which was probably due to the inducing of the arrest in G2/M phase of the cell cycle (P < 0.001). The anti-proliferation and apoptosis inducing effects are more obvious in BCPAP, IHH4 cell lines harboring BRAFV600E mutation. Genistein significantly decreased the invasion of PTC cell lines and partially reverses epithelial mesenchymal transition in PTC cell lines. Functional study indicated that small interfering RNA (siRNA) knockdown of β-catenin significantly reverses the effect of genistein on EMT at protein levels. In conclusion, for the first time, our study suggested that genistein has anticarcinoma effect for PTC patients in the range of 2.5 and 80 μg/ml in thyroid carcinoma cells, which was probably through cytoplasmic translocation of β-catenin. Further study will be needed to determine whether genistein could be used in clinical trial of high-risk PTC.

High expression and localization of β-catenin and epidermal growth factor receptor identify high risk papillary thyroid carcinoma patients

We have evaluated the clinical significance of deregulated expression of β-catenin and epidermal growth factor receptor (EGFR) during papillary thyroid carcinoma (PTC) progression. Immunohistochemical expression of β-catenin and EGFR was analyzed in 104 archival tissues of PTC and 19 matched lymph node metastases (LNMs). β-catenin (39/104, 37.5%) and EGFR (58/104, 55.7%) were co-expressed and co-localized in primary PTCs (p < .0001), which was confirmed by double immunofluorescent staining. The high expression of each molecule, as well as their high cytosolic co-expression, correlated with adverse clinicopathological features of the patients (p < .05). High expression of the proteins did not associate with the presence of BRAFV600E mutation (p > .05), tested by mutant allele-specific PCR amplification. Although nuclear localization of β-catenin was found in a subset of PTC patients (16/104, 15.4%), no β-catenin mutations were found in exon 3 of the CTNNB1 gene (screened by PCR in combination with denaturing gradient gel electrophoresis and confirmed by next generation sequencing). Cases with additional nuclear β-catenin staining showed strong association with high EGFR expression (15/16, 93.7%), the presence of capsule invasion (12/16, 81.25%) and regional LNM (9/16, 52.3%). In corresponding LNMs, β-catenin and EGFR expressions were maintained at high levels or further increased. Co-expression of high levels of β-catenin and EGFR in association with clinicopathological features implicates their clinical utility in risk stratification of PTC patients, and supports the possibility of crosstalk between Wnt/β-catenin and EGFR signaling during PTC progression.

Prognostic significance of diffuse sclerosing variant papillary thyroid carcinoma: a systematic review and meta-analysis.

Diffuse sclerosing variant papillary thyroid carcinoma (DSVPTC) is an uncommon variant of papillary thyroid carcinoma (PTC). The biological behaviors and prognostic outcomes of this variant, however, are still controversial. The aim of this systematic review and meta-analysis is to investigate the prognostic significance and outcomes of DSVPTCs in comparison with classical PTCs (cPTCs). An electronic search was performed in five libraries: PubMed, Scopus, ISI, World Health Organization Global Health Library (WHO GHL) and Virtual Health Library (VHL) in June 2016. Published data were extracted and were pooled into odds ratios (OR), mean differences and corresponding 95% confidence intervals (CI) using random-effect model. Publication bias was analyzed using Egger's regression test and funnel plot observation. From 315 articles, we included 16 articles comprising 732 DSVPTCs for meta-analysis. Overall, DSVPTC manifested more aggressive clinicopathological behaviors than cPTC such as higher rate of vascular invasion (OR: 5.33; 95% CI: 3.08-9.23), extrathyroidal extension (OR: 2.96; 95% CI: 2.04-4.30), lymph node metastasis (OR: 5.40; 95% CI: 2.82-10.35), distant metastasis (OR: 3.61; 95% CI: 1.89-6.88) and were more likely to relapse (OR: 2.83; 95% CI: 1.59-5.05). DSVPTC patients were associated with a worsened overall survival (HR: 1.89; 95% CI: 1.36-2.62). DSVPTCs should be considered high-risk PTCs because of high propensity for tumor invasion, metastasis, relapse and mortality. Aggressiveness of DSVPTCs might be related to a different molecular pathway than that in cPTCs.

Prognosis of papillary thyroid carcinoma in elderly patients after thyroid resection: A retrospective cohort analysis.

The size of the elderly population and the incidence of papillary thyroid carcinoma (PTC) in this group appear to be rapidly increasing, although published information based on more detailed older age groupings are lacking.This study aimed to determine the clinical features and outcomes of elderly patients in PTC.All consecutive patients who received surgery for PTC in our Department from 1978 to 2014 were included. We compared 3 patient groups: young (<65 years), older (65–75 years), and very old patients (>75 years). Total thyroidectomy was performed with lymph node (LN) dissection in most cases, and radioiodine therapy was administered as needed.A total of 3835 patients (3257 young patients, 450 older patients, and 128 very old patients) were identified. Very old patients were more likely to have advanced (III/IV) tumor, nodes, metastases (TNM) stage, greater tumor size, number of tumors, and extracapsular invasion compared with young and older patients. For the 2289 patients with LN dissection (60%), metastatic LNs were more frequent in the very old group (44%) than in the other groups (34% young and 33% older patients) (P = 0.01). Very old patients had more frequent distant metastases (5%) than the older (2%) and young groups (1%) (P < 0.001). The overall postoperative morbidity was not significantly different between the 3 age groups. Recurrence was documented in 202 (6.2%) young, 29 (6.4%) older, and 15 (11.7%) very old PTC patients (P = 0.04). The 5-year disease-free survival was 81.3% for very old, 92.9% for older, and 94.7% for young group (P < 0.001).Very old patients should be considered high-risk PTC patients and their therapeutic strategy may benefit from aggressive treatment.

Timing of Radioactive Iodine Therapy does not Impact Overall Survival in High-Risk Papillary Thyroid Carcinoma

Postthyroidectomy radioiodine (RAI) therapy is indicated for papillary thyroid carcinoma (PTC) with high-risk features. There is variability in the timing of RAI therapy with no consensus. We analyzed the impact of the timing of initial RAI therapy on overall survival (OS) in PTC. The National Cancer Data Base (NCDB) was queried from 2003 to 2006 for patients with PTC undergoing near/subtotal or total thyroidectomy and RAI therapy. High-risk patients had tumors >4 cm in size, lymph node involvement, or grossly positive margins. Early RAI was ≤3 months, whereas delayed was between 3 and 12 months after thyroidectomy. Kaplan-Meier (KM) and Cox survival analyses were performed after adjusting for patient and tumor-related variables. A propensity-matched set of high-risk patients after eliminating bias in RAI timing was also analyzed. There were 9,706 patients in the high-risk group. The median survival was 74.7 months. KM analysis showed a survival benefit for early RAI in high-risk patients (P = .025). However, this difference disappeared (hazard ratio [HR] 1.26, 95% confidence interval [CI] 0.98-1.62, P = .07) on adjusted Cox multivariable analysis. Timing of RAI therapy failed to affect OS in propensity-matched high-risk patients (HR 1.09, 95% CI 0.75-1.58, P = .662). The timing of postthyroidectomy initial RAI therapy does not affect OS in patients with high-risk PTC. CI = confidence interval CLNM = cervical lymph node metastasis FVPTC = follicular variant papillary thyroid carcinoma HR = hazard ratio KM = Kaplan-Meier NCDB = National Cancer Data Base OS = overall survival PTC = papillary thyroid carcinoma RAI = radioactive iodine.

Stomatin-like protein 2 overexpression in papillary thyroid carcinoma is significantly associated with high-risk clinicopathological parameters and BRAFV600E mutation.

Stomatin-like protein 2 (SLP-2), a member of the stomatin protein family, has emerged as a potential molecular hallmark of tumor progression in several human malignancies. The aim of this study was to analyze SLP-2 expression pattern in benign and malignant thyroid tumors (n = 210) and to examine its relationship with clinicopathological parameters and BRAFV600E mutation in thyroid cancer. SLP-2 immunohistochemical expression was not detected in benign adenomas and was absent/weak in follicular and anaplastic carcinomas. High expression levels of SLP-2, found only in papillary thyroid carcinoma (PTC), particularly in the classical variant, were significantly associated with adverse clinicopathological parameters: lymph node metastasis (p = 0.002), extrathyroid invasion (p < 0.001), pT status (p < 0.001), and advanced tumor stage (p = 0.001). Additional genotyping of PTC cases for the BRAFV600E mutation revealed for the first time a close relation between SLP-2 overexpression and the presence of BRAF mutation (p = 0.02) with high positive rates of lymph node metastasis (70%) and extrathyroid invasion (80%) in these cases. The significant association of SLP-2 overexpression with unfavorable clinicopathological characteristics and BRAFV600E mutation indicates that SLP-2 may have a role in aggressiveness of BRAF-mutated PTC and that SLP-2 evaluation could be clinically useful in identification of high-risk PTC patients.

Identification of Intermediate- to High-Risk Papillary Thyroid Carcinoma Patients Who May Be Safely Managed without the Performance of Delayed Stimulated Thyroglobulin Measurements following Total Thyroidectomy and Radioactive Iodine Therapy.

Background. The measurement of stimulated thyroglobulin (sTg) after total thyroidectomy and remnant radioactive iodine (RAI) ablation is the gold standard for monitoring disease status in patients with papillary thyroid carcinomas (PTCs). The aim of this study was to determine whether sTg measurement during follow-up can be avoided in intermediate- and high-risk PTC patients. Methods. A total of 346 patients with PTCs with an intermediate or high risk of recurrence were analysed. All of the patients underwent total thyroidectomy as well as remnant RAI ablation and sTg measurements. Preoperative and postoperative parameters were included in the analysis. Results. Among the preoperative parameters, age below 45 years and preoperative Tg above 19.4 ng/mL were significant risk factors for predicting detectable sTg during follow-up. Among the postoperative parameters, thyroid capsular invasion, lymph node metastasis, and ablative Tg above 2.9 ng/mL were independently correlated with a detectable sTg range. The combination of ablative Tg less than 2.9 ng/mL with pre- and postoperative independent risk factors for detectable sTg increased the negative predictive value for detectable sTg up to 98.5%. Conclusions. Based on pre- and postoperative parameters, a substantial proportion of patients with PTCs in the intermediate- and high-risk classes could avoid aggressive follow-up measures.

Up-regulation of urinary-type plasminogen activator correlates with high-risk papillary thyroid carcinoma with BRAFV600E mutation and its possible molecular mechanism

The aim of the present study is to investigate the relationship between urinary-type plasminogen activator (uPA) expression and clinicopathological features in papillary thyroid carcinoma (PTC) and to determine the signal transduction of PTC cells in vitro.PTC tissues from 42 patients were analyzed for the expression of uPA and the BRAFV600E mutation. BCPAP, a PTC cell line harboring the BRAFV600E mutation, was used to study MAPK signaling. PCR and direct sequencing were applied to analyze BRAFV600E mutation status. uPA mRNA expression was measured using a quantitative RT-PCR method, and uPA protein was localized using an immunohistochemical method. The ERK protein status was detected by Western blot analysis.uPA gene expression was significantly increased in PTC tissues as compared to the corresponding non-tumor tissues. Furthermore, the up-regulation of uPA mRNAs was correlated with high-risk clinicopathological features, including extrathyroid invasion, loss of cellular polarity/cohesiveness, and the BRAFV600E mutation. Marked dephosphorylation of ERK1/2 and down-regulation of uPA expression were detected when BCPAP was treated with a MEK inhibitor, U0126.MEK inhibitors might be a potential treatment strategy for aggressive PTC with BRAFV600E through inhibition of uPA expression.

Evaluation of survivin expression and its prognostic value in papillary thyroid carcinoma

Overexpression of survivin, an inhibitor of apoptosis protein, has been found in a variety of human cancers, and is associated with tumor aggressiveness. In this study, we analyzed the expression of survivin in papillary thyroid carcinoma (PTC) and evaluated its clinical significance for predicting an aggressive course of disease at the time of diagnosis. Survivin expression was determined by immunohistochemistry in 104 tissue specimens of PTC, confirmed by Western blot and correlated with clinicopathological parameters. Of the tumors examined, 74 (71.15%) showed high cytoplasmic survivin expression. There was no association between high survivin expression and age, gender or tumor size. On the other hand, it was closely correlated with the presence of lymph node metastasis (P=0.009), and there was a tendency for correlation with extrathyroidal invasion (P=0.062). The high risk PTC group (TNM stage III–IV) was associated with high levels of survivin (P=0.027). These results indicate that survivin is an unfavorable molecule for PTC prognosis, and that its high expression may indicate a subset of PTC patients with a more aggressive disease course. Evaluation of its expression in fine needle aspiration samples could be a useful tool for the identification of those PTC patients who require more extensive surgery, careful follow-up and therapeutic strategy.

BRAFV600E Mutation Analysis in Papillary Thyroid Carcinoma: Is it Useful for all Patients?

The BRAF(V600E) mutation has been adopted as a prognostic factor in papillary thyroid carcinoma (PTC). However, it remains unclear whether routine BRAF mutation analysis is useful in establishing a prognosis for PTC patients. In the present study we investigated BRAF mutation analysis in a large number of PTC patients with long-term follow-up. We enrolled 766 patients from our hospital who underwent initial surgery for PTC without distant metastasis at diagnosis between 1996 and 2001, and whose BRAF mutation of primary lesions could be analyzed. The average age and follow-up period were 51years and 130months, respectively. To date, 77 (10%) and 37 (5%) patients have developed lymph node and distant recurrence, respectively, and 10 (1%) have died of PTC. The BRAF mutation was positive in 281 patients (37%), and it had no prognostic impact on lymph node recurrence-free (LNRFS) (p=0.700), distant recurrence-free (DRFS) (p=0.696), and cause-specific (CSS) (p=0.125) survival in our entire series. However, CSS of BRAF mutation-positive high-risk patients based on AMES (p=0.030), MACIS (score >6) (p=0.017), the UICC stage (IVa) (p=0.021), CIH classification (Sugitani et al. Surgery 135:139-148, 2004) (p=0.015), and our own classification system (Ito et al. World J Surg 34:2570-2580, 2010) (p=0.010) were significantly poorer than CSS of mutation-negative high-risk patients. The BFAF mutation did not affect CSS of non-high-risk patients, although the incidence of the BRAF mutation did not significantly differ between high-risk and non-high-risk groups based on these classification systems. The BRAF mutation was not related to LNRFS and DRFS in the subsets of high-risk and non-high-risk patients. BRAF mutation analysis is useful in estimating the CSS of high-risk PTC patients based on the representative classification systems. It was not related to the prognosis in non-high-risk patients, at least those living in Japan.

BRAF V600E Mutation Analysis from May-Grünwald Giemsa-Stained Cytological Samples as an Adjunct in Identification of High-Risk Papillary Thyroid Carcinoma

The BRAF(V600E) mutation is specific for thyroid papillary cancer (PTC) and correlates with PTCs invasiveness. This study investigated whether detection of BRAF(V600E) mutation can be performed on routinely stained FNABs. We also examined if establishment of the BRAF(V600E) mutation could help in identification of patients at higher risk for metastatic disease. DNA was isolated from 134 FNABs samples (20 follicular neoplasm, ten suspicious for malignancy, and 104 malignant) using Pinpoint Slide DNA Isolation System. BRAF(V600E) mutation was detected by PCR followed by sequencing. DNA was successfully extracted from all examined FNABs samples. In follicular neoplasm, suspicious for malignancy and malignant FNABs, BRAF(V600E) mutation was found in 0/20 (0%), 2/10 (20%), and 47/104 (45.2%) of cases, respectively. Extra-thyroidal extension was detected in 35/47 (74.4%) BRAF(V600E) positive and in 24/57 (42.1%) wild-type BRAF cases (p = 0.001). Metastases were detected in 37/47 (78.7%) BRAF(V600E) positive and in 28/57 (49.1%) wild-type BRAF cases (p = 0.002). Our results showed that stained FNAB specimens can be used for DNA extraction and assessment of BRAF(V600E) mutation. Detection of BRAF(V600E) mutation had limited value in diagnoses of malignancy in follicular neoplasms but can ascertain malignancy in subset of suspicious for malignancy FNABs. In malignant FNABs, BRAF(V600E) mutation was significantly associated with presence of extra-thyroidal extension and metastases after surgery.

Does Postoperative Thyrotropin Suppression Therapy Truly Decrease Recurrence in Papillary Thyroid Carcinoma? A Randomized Controlled Trial

TSH suppression therapy has been used to decrease thyroid cancer recurrence. However, validation of effects through studies providing a high level of evidence has been lacking. This single-center, open-label, randomized controlled trial tested the hypothesis that disease-free survival (DFS) for papillary thyroid carcinoma (PTC) in patients without TSH suppression is not inferior to that in patients with TSH suppression. Participants were randomly assigned to receive postoperative TSH suppression therapy (group A) or not (group B). Before assignment, patients were stratified into groups with low- and high-risk PTC according to the AMES (age, metastasis, extension, size) risk-group classification. For patients assigned to group A, L-T(4) was administered to keep serum TSH levels below 0.01 μU/ml. TSH levels were adjusted to within normal ranges for patients assigned to group B. Recurrence was evaluated by neck ultrasonography and chest computed tomography. Eligible participants were recruited from 1996-2005, with 218 patients assigned to group A and 215 patients to group B. Analysis was performed on an intention-to-treat basis. DFS did not differ significantly between groups. The 95% confidence interval of the hazard ratio for recurrence was 0.85-1.27 according to Cox proportional hazard modeling, within the margin of 2.12 required to declare 10% noninferiority. DFS for patients without TSH suppression was not inferior by more than 10% to DFS for patients with TSH suppression. Thyroid-conserving surgery without TSH suppression should be considered for patients with low-risk PTC to avoid potential adverse effects of TSH suppression.

MiR-146b is Highly Expressed in Adult Papillary Thyroid Carcinomas with High Risk Features Including Extrathyroidal Invasion and the BRAFV600E Mutation

Papillary thyroid carcinoma (PTC) are clinicopathogenetically heterogeneous. Micro-RNAs (miRNAs) are involved in the pathogenesis of diverse human cancers, including PTC. Information regarding associations between clinicopathological features of PTC with the expression of specific miRNAs, however, is sparse. In this study, we compared expression of deregulated miRNAs in PTCs to assess this was associated with selected clinicopathogenetic features. We analyzed the expression levels of three reported deregulated miRNAs (miR-221, miR-222, and miR-146b) using quantitative real-time polymerase chain reaction in 100 cases of PTCs with distinct clinicopathogenetic characteristics and 16 paired normal controls. The tumor samples were categorized into low- and high-risk groups on the basis of the tumor-node-metastasis staging system. The expression levels of miR-221, miR-222, and miR-146b were significantly associated with extrathyroidal invasion (p = 0.013, 0.05, and 0.003, respectively). The expression levels of miR-221 and miR-146b were significantly higher in the high-risk PTC group (p = 0.01 and 0.042, respectively). The miR-146b expression levels in PTCs with BRAF mutation were significantly higher than those without this mutation (p < 0.0001). There were no other associations between the expression of these miRNAs and other clinicopathological parameters. Our results show the potential importance of miR-221, miR-222, and miR-146b in determining the aggressive properties of PTCs and highlight the need to identify the gene targets of these miRNAs.